Our understanding of programmed macrophage cell death, particularly its role in mediating responses to bacterial pathogens, is an exciting and rapid evolving area of research. While it had long been believed that the cytosol of cells provides a safe sanctuary from host innate immune responses for intracellular pathogens, including Shigella species, these is growing experimental evidence to suggest that this is not the case. For example, recent studies demonstrate that both canonical and non-canonical inflammasomes are activated upon entry of bacteria and/or bacterial PAMPs into the cytosol of intestinal epithelial cells and macrophages, triggering host responses triggering cell death via pyroptosis, an inflammatory lytic process. In addition, at least for Shigella, a professional intracytoplasmic pathogen, apoptosis and necrosis have been implicated to play roles in triggering macrophage cell death. Here we propose to dissect the roles of mammalian host cell cytoplasmic receptors and Shigella determinants in regulating macrophage cell death during the course of an infection. Specifically, in Aim 1, we propose to dissect the human cell death pathways and cytosolic sensors as well as Shigella PAMPs involved in Shigella triggered cell death via pyroptosis, apoptosis and/or necrosis. In Aim 2, we propose to screen for type III secreted Shigella effectors that modulate macrophage cell death using complementary top-down and bottom-up approaches. The successful completion of the proposed studies should not only result in a better understanding of how macrophage ell death is mediated by Shigella, but also expand our understanding of the complex defense counter defense interactions taking place between macrophages and pathogenic bacteria, particularly those armed with pathogenic protein delivery systems.